tbuckley/cabot-search huggingface dataset:
Abstract 10234: HMGCS2-Mediated Ketogenesis Induces Adult Cardiomyocyte Dedifferentiation and Enables Cardiac Regeneration
Authors: Yuan-Yuan Cheng, Zachery Gregorich, Ray P Prajnamitra, David J Lundy, Yi-Chan Lee, Shu-Chian Ruan, Po-Ju Lin, Yu-Ting Yan, Rong Tian, Timothy J Kamp, Patrick C Hsieh
Journal: Circulation (2022)

Introduction: Human cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes (CMs). However, some animals readily regenerate lost myocardium via a process involving CM dedifferentiation, which unlocks their proliferative capacity. Methods: Inspired by this concept, we generated mice with inducible, CM-specific expression of the Yamanaka factors (OSKM), enabling adult CM dedifferentiation in vivo . We profiled changes in CM gene expression by microarray, measured metabolite production by LC-MS and 13 C NMR, and used adeno-associated virus (AAV) to over-express target genes. Cardiac function was measured by echocardiography and intraventricular catheterization. Results: Two days following OSKM induction, adult CMs exhibited a dedifferentiated phenotype and increased proliferation in vivo . Microarray analysis revealed alterations of metabolism-related pathways, particularly an increase of the ketogenic enzyme HMGCS2. Analysis of metabolites confirmed that HMGCS2-induced ketogenesis in adult CMs allowed a metabolic switch from fatty acid oxidation towards ketone utilization. AAV-driven overexpression of HMGCS2 in OSKM mice induced more adult CM dedifferentiation and increased the proliferation rate by two-fold compared to controls. The same phenomenon was observed after myocardial infarction, specifically in the border zone. On the contrary, CM-specific HMGCS2 knockout mice showed poorer baseline cardiac function and impaired recovery following injury. Forced expression of HMGCS2 rescued cardiac function in these mice, thus demonstrating a role of ketogenesis in CM dedifferentiation and proliferation. Conclusions: These data demonstrate the importance of HMGCS2-induced ketogenesis as a means to regulate metabolic response to mammalian cardiac injury, allowing cell dedifferentiation and proliferation as a regenerative response.
Abstract 10515: Mechanical Dyssynchrony in Patients With a Fontan Circulation and Its Relationship to Outcomes
Authors: Addison Gearhart, Sunakshi Bassi, Audrey Dionne, Maxwell P Gold, David M Harrild, Rahul H Rathod, Sunil J Ghelani
Journal: Circulation (2022)

Introduction: The prevalence and significance of mechanical dyssynchrony is not well known in the Fontan population. Methods: Single-center, retrospective analysis of CMRs in Fontan patients compared to healthy controls. Feature tracking was performed on all slices of a short-axis cine stack and dyssynchrony index (DI) was defined as the standard deviation of time-to-peak circumferential strain for all segments. A composite outcome was defined as death, heart transplant listing, or new ventricular arrhythmias. Results: A total of 512 cases (17±9 y) and 42 controls (16±9 y) were included. Figure 1 depicts differences in EDV i , EF, DI, and QRS duration between the cohorts. DI correlated with EDV i (r=0.35; p&lt;0.01), EF (r=-0.29; p&lt;0.01), and QRS duration (r=0.29; p&lt;0.01). At a median follow-up of 4.2 yrs, 10% had death or transplant listing and 4% had ventricular arrhythmias. RV dominance, EDV i , EF, DI, and QRS interval were associated with increased risk of the composite outcome (Table 1). Figure 2 demonstrates a significantly higher probability of the composite outcome in those with EDV i &gt;120 ml/m 2 and DI&gt;70 ms. Conclusion: Fontan patients have more mechanical dyssynchrony and longer QRS duration compared to controls. These abnormalities are more pronounced in RV or mixed ventricular morphology and are associated with a higher risk of ventricular arrhythmias, transplant listing, or death.
Abstract 10888: Toward a Framework for Comparing Inducibility of Reentrant Arrhythmia in Patient-Specific Computational Models to Clinical Atrial Fibrillation Phenotypes
Authors: Fima Macheret, Savannah Bifulco, Griffin Scott, Kirsten Kwan, Yaacoub Chahine, Tanzina Afroze, Nazem W Akoum, Patrick M Boyle
Journal: Circulation (2022)

Introduction: Computational models that incorporate patient-specific left atrial (LA) anatomy and fibrosis from LGE-MRI can assess in silico arrhythmia inducibility in atrial fibrillation (AF) patients. Modeling currently relies on a one-size-fits-all approach for electrophysiological properties, limiting the agreement between simulations and patient outcomes. Hypothesis: Personalization of conduction velocity (ϴ) in computational models of LA fibrosis-mediated arrhythmia derived from persistent AF (PsAF) patients could improve simulation agreement with clinical arrhythmias. Methods: PsAF patients (n=37) were followed ≥2 years after ablation to determine outcomes: AF recurrence, atrial flutter (AFL)-recurrence, or no recurrence (NR). Patient-specific LA models (n=74) were constructed using pre- and ≥90 days post-ablation MRI. Simulated pacing gauged in silico arrhythmia inducibility due to AF-like rotors or AFL-like macro-reentrant tachycardias (MTs). A range of possible ϴ values was tested (±10 or 20%; baseline: non-fibrotic, 71.5 cm/s; fibrotic, 47.0 cm/s). Pre-ablation models were deemed to agree if pacing induced ≥1 rotor or MT; post-ablation models agreed if pacing induced ≥1 rotor, MT, or neither in AF, AFL, or NR patients, respectively. Results: Fifteen patients recurred with AF and 6 with AFL (57% overall). Arrhythmia was induced in 1078/5550 simulations. Using baseline ϴ, model/clinical agreement was 46% (34/74 models), improving to 65% (48/74) when all ϴ values were considered (p=0.031, Fisher’s exact test, Fig. A). ϴ modulation improved model/clinical agreement in both pre- and post-ablation models (Figs. B, C). Pre-ablation model/clinical agreement was higher for patients with more LA LGE (&gt;17.2%) or higher BMI (&gt;32.0 kg/m 2 ) (Fig. D). Conclusions: Patient-specific ϴ calibration improved model/clinical agreement by 41%. Improved understanding of factors that influence model ϴ will have immediate clinical implications.
Abstract 10883: Cigarette Smoking and Mitochondrial Function in Peripheral Artery Disease
Authors: Michelle Guo, Mary M McDermott, Sudarshan Dayanidhi, Christiaan Leeuwenburgh, Stephanie Wohlgemuth, Luigi Ferrucci, Charlotte Peterson, Kate Kosmac, Lu Tian, Lihui Zhao, Robert Sufit, Karen Ho, Michael H Criqui, Shujun Xu, Dongxue Zhang, Philip Greenland
Journal: Circulation (2022)

Introduction: In humans without peripheral artery disease (PAD) and animal models, exposure to cigarette smoke is associated with reduced mitochondrial respiratory function. Many people with PAD smoke cigarettes, but the association of smoking with mitochondrial function in lower extremity skeletal muscle of people with PAD is unknown. Methods: From the Chicago, IL area, 31 people with PAD (ankle brachial index (ABI) &lt; 0.90) were enrolled and consented to gastrocnemius muscle biopsy. Mitochondrial oxidative capacity in gastrocnemius muscle was measured with respirometry. Western blots were performed to quantify mitochondrial membrane abundance via voltage-dependent anion channel (VDAC), mitochondrial biogenesis via peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) , and electron transport chain complexes I-V. Results: Among 31 people with PAD (mean 72.1 years, mean ABI 0.64), 14 (45.2%) smoked cigarettes currently. Participants who currently smoked had higher abundance of PGC-1α (0.75 vs. 0.45 arbitrary units (AU), P&lt;0.01), VDAC (0.62 vs. 0.37 AU, P=0.022), electron transport chain complex I (0.46 vs. 0.21 AU, P=0.031), and complex III (0.76 vs. 0.42 AU, P=0.031), compared to those who did not currently smoke. After normalizing to VDAC, participants who currently smoked had lower mitochondrial oxidative capacity per unit of mitochondrial membrane compared to those who did not currently smoke (complex I+II-mediated oxidative phosphorylation (156.3 vs. 287.0 AU, P=0.017), complex I+II-mediated electron transport chain capacity (184.8 vs. 343.1 AU, P=0.019), complex I-mediated fatty acid oxidative phosphorylation (45.9 vs. 82.1 AU, P=0.034)). After statistical adjustment for age, sex, race, ABI, and body mass index (BMI), most associations were attenuated but remained statistically significant for the higher abundance of VDAC (0.65 vs. 0.35 AU, P=0.037) and complex I (0.50 vs. 0.18 AU, P=0.038) in participants who currently smoked compared to those who did not currently smoke. Conclusions: Results suggest that among people with PAD, current cigarette smoking may stimulate a compensatory increase in mitochondrial biogenesis that may counteract effects of reduced oxidative capacity per unit mitochondrial membrane.
Abstract 10678: Structural and Functional Changes of the Right Ventricle in Sprague Dawley and Wistar Rat Models of Pulmonary Arterial Hypertension
Authors: Liomar A Neves, Paola C Rosas, Hongjian Wang, Peter B Senese, Michael R Gralinski
Journal: Circulation (2022)

Introduction: Assessment of right ventricle (RV) function and structure are essential to determine the efficacy of new PAH drugs preclinically. This study compared RV function, structure, and hemodynamics in response to monocrotaline (MCT) in Sprague Dawley (SD) and Wistar rats. Methods: SD and Wistar rats (194-243 g) were administered either 0.9% NaCl or MCT (60 mg/kg) on Day 0. On Day 23, RV function and structure were evaluated by echocardiography. On Day 24, RV pressure-volume relations were assessed, and heart and lung weights were collected. Results: MCT treatment resulted in dilated RV hypertrophy in both strains, but the magnitude of changes were different between strains. RV internal diameter during diastole (61%, p=0.0003) and systole (67%, p=0.001), RV end-diastolic (51%, p&lt;0.0001) and systolic (80%, p&lt;0.0001) area were greater in MCT/SD than MCT/Wistar. MCT/SD also showed increased right atrial area (110%, p=0.0002) vs. MCT/Wistar. Due to increased load, MCT/SD tended to develop a thicker RV free wall (22%, p&gt;0.05) than MCT/Wistar. Systolic dysfunction was observed with MCT treatment in both strains; however, the MCT/SD showed a greater decrease in RV fractional area change (-51%, p=0.009) than MCT/Wistar. The tricuspid annular velocity and annular plane systolic excursion were slightly decreased in MCT/SD compared to MCT/Wistar (p=NS). RV catheterization showed similar MCT-induced increases in RV end systolic and diastolic pressures in both strains. However, the decrease in cardiac output was more pronounced in MCT/SD (-30%, p&lt;0.0001) than in MCT/Wistar. Increase in RV weight normalized by tibia length (RV/TL) and Fulton’s Index was observed with MCT treatment; but the degree of hypertrophy was more pronounced in MCT/SD (57% RV/TL and 37% Fulton’s Index) than MCT/Wistar. Conclusions: Our results showed that while similar hemodynamic changes were observed in SD and Wistar rats in response to MCT, the magnitude of dilated RV hypertrophy and systolic impairment was exacerbated in SD vs. Wistar rats.
Abstract 10842: Progression of COVID-19 Severity Among SARS-CoV-2 Positive Patients Prescribed Selective Serotonin Reuptake Inhibitors
Authors: Heidi T May, Benjamin D Horne, Stacey Knight, Tami L Bair, Jeffrey L Anderson, Viet T Le, Joseph B Muhlestein, Kirk U Knowlton
Journal: Circulation (2022)

Introduction: The clinical spectrum of COVID-19 can range from asymptomatic to severe, with severe resulting in part from an intense inflammatory response. Selective serotonin reuptake inhibitor (SSRI) is the most commonly prescribed class of antidepressants and has anti-inflammatory and anti-platelet effects. Recent studies reported greater survival and lesser COVID severity in patients taking SSRIs, specifically fluoxetine/fluvoxamine. Recently, application was made to the FDA for emergency use of fluvoxamine to prevent severe COVID-19, but it was denied based on insufficient data. Methods: Patients (n=33,088) testing positive for SARS-CoV-2 between March 14, 2020-December 31, 2021 as outpatients were studied. Patients were matched 3:1 by SSRI prescription at the time of a positive test by propensity score (±0.001). Patients were evaluated for COVID-19 hospitalization within 14-days and death within 3-months of positive SARS-CoV-2 test. Results: A total of 8,272 SSRI patients were well-matched to 24,816 no SSRI patients (Table 1). Hospitalization and death were significantly greater in the SSRI group compared to the no SSRI group (Table 1). A total of 2,067 (25.0%) of SSRI patients were taking fluoxetine or fluvoxamine. While attenuated, no SSRI remained associated with a lower 14-day COVID-19 hospitalization risk when compared to fluoxetine or fluvoxamine use, but not with 3-month death (Table 2). Conclusion: This study did not find a lower risk of progression of COVID-19 severity with the use of any SSRI or fluoxetine/fluvoxamine alone. Results from this study support the FDA’s decision to not recommend their use at an early stage of a COVID-19 infection.
Abstract 10532: Physician Interpretation and Characterization of Intracardiac Electrograms at the Time of Non-Cardiac Death
Authors: Daniel S Kikuchi, Soroosh Kiani, Neal K Bhatia, Rand Ibrahim, Faisal M Merchant, Mithun Suresh, Anand D Shah, Mikhael F El-Chami, Angel R Leon, Michael S Lloyd
Journal: Circulation (2022)

Introduction: Electrograms (EGMs) generated by implantable cardiac devices at the time of non-cardiac death may have artifact from non-arrhythmic sources, such as coagulated blood and air bubbles. While few studies have described the nature of terminal EGMs in non-cardiac death, it is clinically and medicolegally important to characterize these EGMs to elucidate events that may otherwise be misinterpreted as device failure. Here we investigated terminal EGM features that may aid clinicians in discerning cardiac from non-cardiac death. Methods: Terminal EGMs were analyzed by independent physician reviewers. Deaths were adjudicated as non-cardiac based on direct clinical data at the time of death using a modified Cardiac Arrhythmia Suppression Trial approach. In total, 16 non-cardiac terminal EGMs were identified and compared to a control cohort of true arrhythmic events. Using a subset of identified EGMs, an 8-question survey was administered to electrophysiologists blinded to cause of death. Several variables were identified as important for the correct classification of EGMs. The statistical performance of each variable for detecting non-cardiac death and true arrhythmias in our sample was evaluated. These results were shared, and the survey was readministered. Results: In our sample, absence of organized atrial activity had a sensitivity (SN) of 78.5%, specificity (SP) of 100%, and positive predictive value (PPV) of 100% for non-cardiac terminal EGMs. Cycle length &lt;130 ms and absence of discernible deflections both had SPs and PPVs of 100% for non-cardiac death but were less sensitive (60% and 20%, respectively). An abrupt change following therapy and response to therapy both had SNs, SPs, and PPVs of 100% for true arrhythmias. Survey response rate was 68.8% and 62.5% for the pre- and post-survey, respectively. Pre-survey scores ranged from 50 – 87.5% correct with a mean of 72.7%. Post-survey scores ranged from 75 – 100% with a mean of 86.3% (p&lt; 0.01). Conclusions: There is variability and inaccuracy among expert physicians' interpretation of EGMs during non-cardiac death. The variables identified in this study will aid in the development of a clinical risk score used to discern non-cardiac death and true device malfunction based on terminal EGMs.
Abstract 10249: Infective Endocarditis: A Diagnostic Challenge
Authors: Jemi Galani, Hassan Chami, Colleen Kraft
Journal: Circulation (2022)

Case: A healthy 30-year-old female with past medical history of eczema and no prior cardiac history presented with altered mental status, fever, neck stiffness and photophobia. Blood and CSF cultures grew methicillin susceptible Staphylococcus aureus , and the patient was started on nafcillin and linezolid. Bacteremia source was unclear, presumed to be minor skin breaks on her hands. MRI brain revealed multiple cerebral septic emboli, prompting concern for infective endocarditis. However, TTE and TEE were negative for vegetations, valve thickening, and valvular regurgitation. Blood cultures remained positive for MSSA despite dual antibiotic therapy and by hospital day 4, she began experiencing shortness of breath and new Janeway lesions were noted on exam. Repeat TTE and TEE were also negative for endocarditis. To further evaluate for an arterial source of seeding, CTA chest/abdomen was obtained which was unremarkable. Given persistence of bacteremia despite dual antibiotic therapy and unknown left-sided source, whole body PET CT scan was obtained which showed focal FDG uptake in the mitral annulus/valve region. Repeat TEE the following day showed a mitral valve ring abscess, a 1.2x0.4cm vegetation involving the P3 segment of the mitral valve, perforation at the mitral valve annulus, and new moderate mitral regurgitation. After a risk benefit discussion, the patient opted for conservative management with serial monitoring over surgical repair. She was treated with six weeks of nafcillin and four weeks of linezolid. Most recent TEE showed resolution of valvular abscess and vegetation with continued moderate mitral regurgitation. Discussion: We present a case of high grade MSSA endocarditis in a young, healthy patient without pre-existing valvular disease, causing mitral valve perforation. Infective endocarditis remains a challenging diagnosis, and this case highlights the diagnostic utility of&amp;nbsp;FDG PET CT scan in such complex cases.
Abstract 10266: T-Wave Features Predict Functional Worsening in Children With Pulmonary Arterial Hypertension: Machine Learning Insights From Standard ECG
Authors: Michal Schafer, Caitlin Brateng, Benjamin Frank, Kendall Hunter, Kathryn Collins, Matthew Stone, Max B Mitchell, Dunbar D Ivy, Johannes von Alvensleben
Journal: Circulation (2022)

Introduction: Various T-wave characteristics have been shown to be predictive of ventricular diastolic dysfunction and sudden cardiac death in adults. However, specific T-wave morphologies and their predictive potential in pediatric patients is unknown. Hypothesis: Machine learning derived T-wave characteristics will be different between children with pulmonary arterial hypertension (PAH) and healthy controls. Furthermore, T-wave characteristics will be predictive of clinical functional worsening in PAH patients. Methods: Principal component analysis (PCA) was applied to ECGs collected for children with PAH (n=155) at the time of diagnostic catheterization and matched healthy controls (n=47) to describe basic T-wave characteristics. Patients (&lt;18 y/o) with PAH were defined as a mean pulmonary pressure &gt;25 mmHg in the absence of obstructive left heart disease. Interpreted T-wave features were then compared between PAH and control groups. Identified T-wave measurements underwent survival analysis using standardized PAH functional class worsening as a clinical endpoint. Results: Identified T-wave principal components were 1) T-wave height and 2) early or late incidence of T-wave peak (FIGURE- 1A). The second principal component was associated with PAH diagnostic specificity (94%). Time from T-wave peak to T-wave end (TpTe) as measured in leads V4 to V6 was significantly higher in children with PAH (all P &lt; 0.001) (FIGURE - 1B). V4 derived TpTe value &gt; 132 ms and V5 derived TpTe value &gt; 135 ms were associated with the higher probability of clinical functional worsening (P = 0.018 and P = 0.002, respectively) (FIGURE - 1C). Conclusions: T-wave features derived from standard ECG are 1) different between children with PAH and their healthy peers and 2) predictive of clinical functional worsening.
Abstract 10579: Prevalence and Morphology of Premature Ventricular Contractions on Routine Athletic Electrocardiogram Screening
Authors: Sofia E Gomez, Marco V Perez, Matthew Wheeler, David M Hadley, Calvin Hwang, Andrea L Kussman, Daniel Kim, Vic Froelicher
Journal: Circulation (2022)

Introduction: The clinical implications of incidental premature ventricular contractions (PVCs) are poorly understood. Though controversial, athletes often receive electrocardiograms (ECGs) during pre-participation exams. The prevalence and morphologies of PVCs in this cohort have not been widely reported. Recent studies have defined benign PVC morphologic patterns in athlete populations that may guide clinical evaluations. Methods: Digital ECGs were obtained from 10,728 screened athletes aged 14 to 35 at school and professional team screenings in California. Captured PVCs were analyzed using simultaneous frontal and horizontal plane leads, displaying each standard ECG lead in full-length, allowing for morphologic categorization. PVCs were coded for morphology and benign status using recommended criteria outlined in Figure 1. Results: Twenty-six of 10,728 athletes (0.24%) had at least one PVC (Figure 1); 7 of those (27%) had bigeminy and 3 of those (12%) had trigeminy. Overall, participants were 43% female, 62% White, 12% Black, 9% Asian, and 8% Hispanic. Of those with PVCs, 50% were female, 65% were White, 23% were Black, 8% were Asian, and 4% were Hispanic. Twenty-four ECGs (92%) had PVCs with benign patterns, including 17 with right ventricular outflow tract, 5 with left anterior fascicle, and 2 with left posterior fascicle morphology. Two ECGs had non-benign PVCs with left bundle branch patterns and superior axes. Both of these athletes had normal echocardiograms and exercise testing and are being followed closely. Conclusions: We found a low prevalence of PVCs on routine ECG screening of young athletes, although evaluation of PVC prevalence and frequency are limited by the short duration of an ECG. Most incidental PVCs among young athletes had benign patterns. This study also demonstrates the value of digital ECG recorders to display simultaneous frontal and horizontal plane leads for the morphologic categorization of PVCs which may guide further workup.